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Background: There have been no standardized surgical options for severe scoliotic curvatures ≥100°. Halo-gravity traction is a viable option for surgical treatment of severe scoliosis. The aim of this study was to evaluate the efficacy and safety of perioperative halo-gravity traction for scoliosis curves ≥100° with respect to radiographic outcomes and clinical complications. Methods: A total of 21 scoliosis patients with ≥100° curves (average 118.7°; range 100°-158°) with a minimum 2-year follow-up (average 41.8 months; range 24.0-97.0 months) who underwent spinal instrumented fusion using perioperative halo-gravity traction were analyzed. Diagnoses were neuromuscular scoliosis (n = 10), idiopathic (n = 9), and congenital (n = 2). In all, 15 patients were treated by the anterior release procedure followed by final posterior fusion and 6 patients by posterior fusion alone. Six patients had only preoperative traction preceding posterior fusion alone, 6 patients only staged traction between anterior release and final posterior fusion, and 9 patients had both preoperative traction preceding anterior release and staged traction preceding final posterior fusion. The average overall traction period in all patients was 67 days (range 10-78 days). Results: Radiographic outcomes demonstrated 51.3% correction of the major Cobb angle, 40 mm correction of apical vertebral translation, 76 mm increase of T1-S1 length, and 20.7% increase of space available for lungs at the ultimate follow-up (all comparisons P < 0.05). Preoperative traction demonstrated 27.5% correction of the major curve Cobb angle, 51.5 mm increase of T1-S1 length, 14.9% increase of space available for the lungs (all comparisons P < 0.05). Staged traction after anterior release demonstrated 37.2% correction of the major curve Cobb angle, 26.1 mm correction of apical vertebral translation, 56.5 mm increase of T1-S1 length, 14.2% increase of space available for the lungs (all comparisons P < 0.05). There were only two patients with a pin-site problem, and one required débridement. There were no neurological deficits or clinical complications. Conclusions: Scoliosis patients with ≥100° curves can be managed successfully by corrective fusion surgery concomitant with perioperative halo-gravity traction without significant complications. [ABSTRACT FROM AUTHOR]

Background: Patterns-of-care studies emphasize significant variation in the management of lung cancer. The aim of the study was to compare the patterns of care for patients diagnosed with lung cancer in 1996 and 2002 within three health areas in New South Wales. Methods: Treatment data were collected from medical records and treating doctors for the calendar year 1996 and between 1 November 2001 and 31 December 2002. Patients were residents of either south-western Sydney, Hunter or Northern Sydney health areas at the time of diagnosis. χ2-tests were used to investigate changes in treatment patterns between the two time periods. An adjusted odds ratio for treatment in 2002 relative to 1996 was calculated using logistic regression. Results: Data were available for 738 and 567 cases in 1996 and 2002, respectively. Cancer-specific therapy was given within 6 months of diagnosis to 62 and 64% of patients, respectively. Adjusting for health area, age, sex, pathology and performance status, the odds ratio (OR) of treatment in 2002 relative to 1996 was 1.03 (95% confidence interval (CI) 0.78–1.35). When stage was included, the odds of treatment in 2002 relative to 1996 for non-small-cell lung cancer ( n = 950) was 1.21 (95%CI 0.87–1.68). After adjustment for potential confounders, patients diagnosed with small-cell lung cancer ( n = 176) were substantially less likely to receive treatment in 2002 compared with patients diagnosed in 1996 (OR = 0.11; 95%CI 0.04–0.34). Conclusion: The odds of receiving treatment in 2002 and 1996 were similar. However, patients diagnosed with small-cell lung cancer in 2002 were significantly less likely to receive treatment. Overall, this study suggests there has been no change in lung cancer care in New South Wales. Further work is required to determine what proportion of persons with lung cancer should receive cancer-specific treatment so that clinical practices can be judged appropriately. [ABSTRACT FROM AUTHOR]

Abstract: Objective. : Recent studies have suggested that the definition of optimal cytoreduction for advanced EOC should be changed from the current Gynecologic Oncology Group threshold of ≤1 cm residual disease to no gross residual disease owing to improved survival of patients (pts) rendered macroscopically disease-free. The objective of this study was to analyze survival rates at very specific residual disease diameters to determine the optimal goal of primary cytoreduction for bulky stage IIIC EOC. Methods. : A prospectively kept database was used to identify and review the records of all pts with Stage IIIC EOC who underwent primary cytoreductive surgery at our institution between January 1989 and December 2003. To analyze a homogeneous cohort of cases, we excluded pts with stage IIIC disease based on nodal metastasis alone (without bulky abdominal tumor), fallopian tube or primary peritoneal carcinomas, and borderline tumors. Standard statistical analyses were utilized. Results. : The study cohort included 465 pts. The median age was 60 years (range, 25–87), and the median follow-up was 38 months (range, 1–199). Univariate and multivariate analyses, which included various prognostic factors, identified amount of residual disease as a significant prognostic factor (P < 0.001). Median overall survival in relation to the 5 residual disease categories was: no gross residual, 106 months; gross ≤0.5 cm, 66 months; 0.6–1.0 cm, 48 months; 1–2 cm, 33 months; >2 cm, 34 months. Statistical comparison between the 5 residual disease categories revealed 3 distinct groups with significantly different survival rates (P < 0.01). These 3 groups were: (1) no gross residual; (2) gross ≤1 cm residual; and (3) >1 cm residual. Although the difference in survival did not reach statistical significance, within the gross ≤1 cm residual group, there was a trend toward improved survival in pts left with smaller volume, ≤0.5 cm residual compared with those with 0.6–1.0 cm residual (P = 0.06). Conclusion. : Our data suggest that removal of all evidence of macroscopic disease is associated with prolonged survival and should be the goal of primary cytoreductive surgery. If complete gross resection is not feasible, however, cytoreduction to as minimal residual tumor as possible should be the focus of cytoreductive efforts, as each incremental decrease in residual disease below 1 cm may be associated with an incremental improvement in overall survival. [Copyright &y& Elsevier]

This study was designed to investigate the biochemical and physiological covariates or comedications that affect the pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia (CP CML). Pharmacokinetic data were analyzed in 371 patients receiving 400 mg imatinib once daily during a phase III trial of imatinib vs interferon-alfa plus cytarabine for the treatment of newly diagnosed CP CML. Covariates included age, weight, sex, ethnicity, haemoglobin (Hb) concentration, white blood cell (WBC) count, liver function, and creatinine concentration. Blood samples for imatinib analysis were taken on treatment days 1 and 29. Nonlinear mixed effects modelling was used for the population pharmacokinetic analysis. Population mean estimates (95% confidence interval) at day 1 for apparent clearance (CL) and apparent volume of distribution ( V) of imatinib were 14 (13-15) l h−1 and 252 (237-267) l, respectively. Modelling suggested that CL decreased by 4 (3-5) l h−1 from day 1 to day 29, whereas V remained unchanged. Interindividual variability in CL and V was 32% and 31%, respectively. Weight, Hb, and WBC count demonstrated small effects on CL and V. Doubling body weight or Hb or halving the WBC count was associated with a 12%, 86% and 8% increase in CL, respectively, and a 32%, 60% and 5% increase in V, respectively. Comedications showed no clear effects on imatinib CL. Population covariates and coadministered drugs minimally affected imatinib pharmacokinetics in newly diagnosed CP CML patients. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer deaths in New South Wales (NSW). The incidence of and mortality from lung cancer differ throughout different area health services in NSW.To compare patterns of care in lung cancer among three area health services in NSW.South-western Sydney Area Health Service (SWSAHS), Northern Sydney Area Health Service (NSAHS) and Hunter Area Health Service (HAHS)­residents diagnosed with lung cancer in 1996 were identified from the NSW Central Cancer Registry and their medical records were reviewed. The main outcome measures were specialist care, investigations, treatment and survival.The study population comprised 256 SWSAHS, 270 NSAHS and 212 HAHS residents. NSAHS residents were older, with a median age of 73 years compared with 68 years in SWSAHS and 70 years in HAHS (P = 0.001). The performance status and stage distributions of the populations were similar. Twenty per cent of HAHS residents did not have a pathological diagnosis compared with 10% in SWSAHS and 9% in NSAHS (P = 0.005). Forty-five per cent of HAHS residents received no treatment compared with 25 and 22% in SWSAHS and NSAHS, respectively (P < 0.001). Despite these differences, there was no significant difference in overall survival.Lung cancer patterns of care were significantly different among the areas. The variability of practice identified in this study needs to be addressed to ensure optimum care for all patients with lung cancer. Although there was no significant difference in survival, under-utilization of efficacious treatment is likely to have affected patients’ quality of life. (Intern Med J 2004; 34: 677−683) [ABSTRACT FROM AUTHOR]

Introduction: Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung injury. The impact of pre-existing chronic obstructive pulmonary disease (COPD) or emphysema on ARDS pathogenesis is not well characterized., Methods: Secondary analysis of ARDS patients enrolled in the Acute Lung Injury Registry and Biospecimen Repository at the University of Pittsburgh between June 2012 and September 2021. Patients were categorized into two mutually exclusive groups by the prevalence of COPD or emphysema at the time of ARDS diagnosis. The COPD/emphysema group comprised ARDS patients with radiological evidence of emphysema, chart diagnosis of COPD, or both. Demographics, lung mechanics, and clinical outcomes were obtained from the electronic medical record. Host-response biomarkers known to have validated associations with ARDS were previously measured in plasma and lower respiratory tract samples using a customized Luminex assay. Continuous and categorical variables were compared between groups with and without COPD/emphysema., Results: 217 patients with ARDS were included in the study, 57 (27%) had COPD/emphysema. Patients with COPD/emphysema were older (median 62 [interquartile range 55-69] versus 53 [41-64] years, p < 0.01), more likely to be male (62% vs. 44%, p = 0.02) and had a higher prevalence of congestive heart failure (25% vs. 4%, p < 0.01) compared to patients without COPD/emphysema. Baseline demographics, laboratory parameters, and mechanical ventilatory characteristics were otherwise similar between the two groups. No difference in 90-day mortality was observed between groups; however, patients with COPD/emphysema had shorter duration of intensive care unit (ICU) stay (median 10 [7-18] versus 16 [9-28] days, p = 0.04) and shorter duration of mechanical ventilation (median 7 [4-16] vs. 12 [6-20] days, p = 0.01). Host response biomarkers in serum and lower respiratory tract samples did not significantly differ between groups., Conclusion: ARDS patients with COPD or emphysema had similar respiratory mechanics, host response biomarker profiles, and mortality compared to those without COPD or emphysema but with a shorter median duration of mechanical ventilation and ICU length of stay. Future studies should address differences in clinical and biological responses by disease severity, and should investigate the impact of severity of COPD and emphysema on mechanical ventilation and targeted therapeutic strategies in ARDS., Clinical Trial Number: Not applicable., (© 2024. The Author(s).)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background: Hospitalized patients with severe COVID-19 follow heterogeneous clinical trajectories, requiring different levels of respiratory support and experiencing diverse clinical outcomes. Differences in host immune responses to SARS-CoV-2 infection may account for the heterogeneous clinical course, but we have limited data on the dynamic evolution of systemic biomarkers and related subphenotypes. Improved understanding of the dynamic transitions of host subphenotypes in COVID-19 may allow for improved patient selection for targeted therapies., Research Question: We examined the trajectories of host-response profiles in severe COVID-19 and evaluated their prognostic impact on clinical outcomes., Study Design and Methods: In this prospective observational study, we enrolled 323 inpatients with COVID-19 receiving different levels of baseline respiratory support: (1) low-flow oxygen (37%), (2) noninvasive ventilation (NIV) or high-flow oxygen (HFO; 29%), (3) invasive mechanical ventilation (27%), and (4) extracorporeal membrane oxygenation (7%). We collected plasma samples on enrollment and at days 5 and 10 to measure host-response biomarkers. We classified patients by inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker, and subphenotype trajectories and outcomes during hospitalization., Results: IL-6, procalcitonin, and angiopoietin 2 persistently were elevated in patients receiving higher levels of respiratory support, whereas soluble receptor of advanced glycation end products (sRAGE) levels displayed the inverse pattern. Patients receiving NIV or HFO at baseline showed the most dynamic clinical trajectory, with 24% eventually requiring intubation and exhibiting worse 60-day mortality than patients receiving invasive mechanical ventilation at baseline (67% vs 35%; P < .0001). sRAGE levels predicted NIV failure and worse 60-day mortality for patients receiving NIV or HFO, whereas IL-6 levels were predictive in all patients regardless of level of support ( P < .01). Patients classified to a hyperinflammatory subphenotype at baseline (< 10%) showed worse 60-day survival ( P < .0001) and 50% of them remained classified as hyperinflammatory at 5 days after enrollment., Interpretation: Longitudinal study of the systemic host response in COVID-19 revealed substantial and predictive interindividual variability influenced by baseline levels of respiratory support.

Secondary infection (SI) diagnosis in severe COVID-19 remains challenging. We correlated metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) with clinical SI assessment, immune response, and outcomes. We classified 42 COVID-19 inpatients as microbiologically confirmed-SI (Micro-SI, n = 8), clinically diagnosed-SI (Clinical-SI, n = 13, i.e., empiric antimicrobials), or no-clinical-suspicion-for-SI (No-Suspected-SI, n = 21). McfDNA-Seq was successful in 73% of samples. McfDNA detection was higher in Micro-SI (94%) compared to Clinical-SI (57%, p = 0.03), and unexpectedly high in No-Suspected-SI (83%), similar to Micro-SI. We detected culture-concordant mcfDNA species in 81% of Micro-SI samples. McfDNA correlated with LRT 16S rRNA bacterial burden (r = 0.74, p = 0.02), and biomarkers (white blood cell count, IL-6, IL-8, SPD, all p < 0.05). McfDNA levels were predictive of worse 90-day survival (hazard ratio 1.30 [1.02-1.64] for each log 10 mcfDNA, p = 0.03). High mcfDNA levels in COVID-19 patients without clinical SI suspicion may suggest SI under-diagnosis. McfDNA-Seq offers a non-invasive diagnostic tool for pathogen identification, with prognostic value on clinical outcomes., Competing Interests: Drs. Duttagupta and Ahmed were employed by Karius, Inc at the time of the study but are no longer employed by Karius, Inc. Drs. Kitsios and Haidar have received research funding from Karius, Inc. Drs. Kitsios and Morris have received research funding from Pfizer, Inc. Dr. Haidar serves on the Karius, Inc scientific advisory board. Dr. Mellors is a consultant to AlloVir, Infectious Disease Connect, Inc., and Gilead Sciences, Inc., has received research funding from Gilead Sciences, Inc. to the University of Pittsburgh, receives compensation from Abound Bio, Inc. (unrelated to the current work) and holds shares options in Galapogos, Infectious Disease Connect, Inc., and MingMed Biotechnology Co. Ltd. (unrelated to the current work). Dr. McVerry has received research funding from Bayer Pharmaceuticals, Inc. and consulting fees from Boehringer Ingelheim, both unrelated to this work., (© 2023 The Authors.)

We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study., Competing Interests: Potential conflicts of interest. G. H. reports research grants from AlloVir, Inc, Karius, the National Institutes of Health, and AstraZeneca; consulting fees for serving on the advisory boards of Karius and AstraZeneca; and honoraria from MDOutlook. Y. S. H. is supported by the Hillman Fellowship for Innovative Cancer Research. F. P. S. reports research grants from Ansun, Regeneron, and Merck and serves on the advisory boards for Takeda and Eurofins Viracor. A. M. L. is a cofounder and equity holder in AlloVir, Inc, and Marker Therapeutics and a consultant for AlloVir, Inc. W. L. M. and E. A. are former employees and current stockholders of AlloVir, Inc. M. M. and B. P. are current employees of AlloVir, Inc. J. W. M. is a consultant to Gilead Sciences, Inc; reports grant funding from Gilead Sciences, Inc, to the University of Pittsburgh and compensation from Abound Bio, Inc (unrelated to the current work); and has share options in Infectious Disease Connect, Inc, and Galapagos, NV (unrelated to the current work). All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Our prior research showed that patient experience-as reported by Google, Yelp, and the Hospital Consumer Assessment of Healthcare Providers and Systems survey-is associated with health outcomes. Upon learning that COVID-19 mortality rates differed among U.S. geographic areas, we sought to determine if COVID-19 outcomes were associated with patient experience. We reviewed daily, U.S.-county-level-accrued COVID-19 infections and deaths during the first year of the pandemic using each locality's mean online patient review rating, correcting for county-level demographic factors. We found doctor star ratings were significantly associated with COVID-19 outcomes. We estimated the absolute risk reduction (ARR) and relative risk reduction (RRR) for each outcome by comparing the real-world-observed outcomes, observed with the mean star rating, to the outcomes predicted by our model with a 0.3 unit higher average star rating. Geographic areas with higher patient satisfaction online review ratings in our models had substantially better COVID-19 outcomes. Our models predict that, had medical practices nationwide maintained a 4-star average online review rating-a 0.3-star increase above the current national average-the U.S may have experienced a nearly 11% lower COVID-19 infection rate and a nearly 17% lower death rate among those infected.

Background: Insomnia Disorder is characterized by high degree of phenotypic heterogeneity, that might influence treatment response., Methods: 123 of 294 insomnia patients initially recruited (66.7% females, age=40.59±11.89) were assessed before and after group Cognitive-Behavioral Therapy for Insomnia (CBT-I), as well as at follow-up (7.8±1.6 years after the end-of-treatment). By use of latent class analysis (LCA) we identified insomnia subtypes according with baseline scores of insomnia severity and features, anxiety, depression, stress and sleepiness symptoms, circadian rhythm, and treatment effectiveness (Delta score of Insomnia Severity Index-ISI between baseline and end-of-treatment)., Results: By LCA we revealed three classes: "PURE INSOMNIA", "INSOMNIA+ANXIETY+DEPRESSION+STRESS", and "INSOMNIA+ANXIETY". The improvements in insomnia severity was maintained up to 10 years after the end-of-treatment, but with differences between classes (p<0.05). Class "INSOMNIA+ANXIETY+DEPRESSION+STRESS" showed at the end-of-treatment the largest percentage of responders (63.5% = Insomnia Severity Index decrease ≥8). However, at follow up the effect was less and 48.1% had a moderate or severe insomnia (Insomnia Severity Index >14)., Limitations: The lack of a control group and the absence of a complete clinical assessment at the follow-up limit the interpretability of our results., Conclusions: Our data driven analysis suggest insomnia heterogeneity can be categorized into sub-classes by depression, anxiety, and stress symptoms. In addition, insomnia patients with stress and depression symptoms maintained highest percentage of clinical depression at the end-of-treatment and insomnia at follow-up, in comparison with others classes. Stress and depression symptoms should be considered risk factors that play an important role in the long-term outcome of CBT-I., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective To explore end-of-life care in the ward and intensive care unit (ICU) environment in nine Australian hospitals in a retrospective observational study. Methods In total, 1693 in-hospital deaths, 356 in ICU, were reviewed, including patient demographics, advance care plans, life-sustaining treatments, recognition of dying by clinicians and evidence of the palliative approach to patient care. Results Most patients (n =1430, 84%) were aged ≥60 years, with a low percentage (n =208, 12%) having an end-of-life care plan on admission. Following admission, 82% (n =1391) of patients were recognised as dying, but the time between recognition of dying to death was short (ICU (staying 4-48h) median 0.34 days (first quartile (Q1), third quartile (Q3): 0.16, 0.72); Ward (staying more than 48h) median 2.1 days (Q1, Q3: 0.96, 4.3)). Although 41% (n =621) patients were referred for specialist palliative care, most referrals were within the last few days of life (2.3 days (0.88, 5.9)) and 62% of patients (n =1047) experienced active intervention in their final 48h. Conclusions Late recognition of dying can expose patients to active interventions and minimises timely palliative care. To attain alignment to the National Consensus Statement to improve experiences of end-of-life care, a nationally coordinated approach is needed. What is known about the topic? The majority of Australian patient deaths occur in hospitals whose care needs to align to the Australian Commission on Safety and Quality in Health Care's National Consensus Statement, essential elements of safe and high -quality end -of -life care. What does this paper add? The largest Australian study of hospital deaths reveals only 12% of patients have existing advance care plans, recognition of death is predominantly within the last 48h of life, with 60% receiving investigations and interventions during this time with late symptom relief. What are the implications for practitioners? Given the poor alignment with the National Consensus Statement, a nationally coordinated approach would improve the patient experience of end-of-life care.

Objective: The purpose of this meta-analysis is to gather and investigate pooled information on the responsiveness of the main patient outcome measure in cardiac rehabilitation (CR) and pulmonary rehabilitation (PR). The main outcome measure in CR and PR has been found to be the Medical Outcomes Study Short Form-36 health survey (SF-36)., Data Sources: A previous systematic effectiveness review of this literature was used as the basis of this statistical analysis, with the bulk of articles being observational studies., Study Selection: This meta-analysis assessed articles on CR that used SF-36 pre and post "within" (per interventional group) mean scores and in the PR literature that used the SF-36 and the Chronic Respiratory Questionnaire (CRQ) "within" change scores., Data Extraction: Each group of patients in the chosen literature were taken to represent a single group, so that studies such as randomized controlled trials were listed twice. We undertook a correlation analysis between SF-36 pre and post "within" mean scores in the CR literature. In the PR literature, we undertook a correlation analysis between SF-36 and the CRQ "within" change scores; this involved Spearman correlation coefficients., Data Synthesis: The SF-36 Mental Composite Score domain is the most responsive of the composite SF-36 domains, with the Physical Composite Score showing less ability to discriminate in the higher SF-36 scores. In the individual domains, Role Emotional scored r =0.52, P ≤.001 with only 27% of the variance explained, and Role Physical with r =0.49, P ≤.005 had only 24% of the variance explained. In the PR literature Spearman rank correlation coefficient shows that SF-36 Physical Composite Score has a weaker correlation to the CRQ at 0.39 than the SF-36 Mental Composite Score, which was 0.63., Conclusions: This suggests that the SF-36 is not suited as a pre- to postprogram assessment tool for CR and PR. More studies, however, need to be conducted particularly in CR with regard to the responsiveness of the SF-36., (© 2021 The Authors.)

Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are two common chronic diseases with a well-documented association. Whether the association is causal has been highlighted by recent evidence reporting a neurobiological link between these disorders. This narrative review discusses the brain regions and networks involved in OSA as potential vulnerable areas for the development of AD neuropathology with a particular focus on gender-related implications. Using a neuroimaging perspective supported by neuropathological investigations, we provide a new model of neurodegeneration common to OSA and AD, that we have called OSA-AD neurodegeneration in order to decode the causal links between these two chronic conditions.

Idiopathic pulmonary fibrosis (IPF) is a fatal and incurable form of interstitial lung disease in which persistent injury results in scar tissue formation. As fibrosis thickens, the lung tissue loses the ability to facilitate gas exchange and provide cells with needed oxygen. Currently, IPF has few treatment options and no effective therapies, aside from lung transplant. Here we present a series of studies utilizing lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) by inhalation to treat different models of lung injury and fibrosis. Analysis reveals that LSC-Sec and LSC-Exo treatments could attenuate and resolve bleomycin- and silica-induced fibrosis by reestablishing normal alveolar structure and decreasing both collagen accumulation and myofibroblast proliferation. Additionally, LSC-Sec and LSC-Exo exhibit superior therapeutic benefits than their counterparts derived from mesenchymal stem cells in some measures. We showed that an inhalation treatment of secretome and exosome exhibited therapeutic potential for lung regeneration in two experimental models of pulmonary fibrosis.

Metastasis accounts for the majority of all cancer deaths, yet the process remains poorly understood. A pivotal step in the metastasis process is the exiting of tumor cells from the circulation, a process known as extravasation. However, it is unclear how tumor cells extravasate and whether multicellular clusters of tumor cells possess the ability to exit as a whole or must first disassociate. In this study, we use in vivo zebrafish and mouse models to elucidate the mechanism tumor cells use to extravasate. We found that circulating tumor cells exit the circulation using the recently identified extravasation mechanism, angiopellosis, and do so as both clusters and individual cells. We further show that when melanoma and cervical cancer cells utilize this extravasation method to exit as clusters, they exhibit an increased ability to form tumors at distant sites through the expression of unique genetic profiles. Collectively, we present a new model for tumor cell extravasation of both individual and multicellular circulating tumor cells.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Background: Cardiac and pulmonary rehabilitation have been shown to reduce the symptoms of disease, as well as reducing health care utilization. To ensure the continuation of these programs, patient outcome measures (POMs) are essential to map treatment effectiveness. This review is a comparative effectiveness literature review of studies with a pre- to post-POM assessment of responsiveness (ie, change in health status over time)., Methods: A quality review of the literature included not only randomized controlled trials but also parallel studies, as well as all observational and retrospective trials. This review included a list of articles and their characteristics; a quality assessment of the literature and a list of POMs utilized in this setting were assessed for responsiveness., Results: There was inconsistency in the literature with the measurement of responsiveness or effect size. The most commonly used POM was the SF-36; however, it was found to be less responsive to change in health status pre- to post-rehabilitation, particularly in the mental domain of this instrument. The most responsive POM in this setting was the Global Mood Scale., Conclusion: The surveyed literature found no "gold standard" POM for either cardiac rehabilitation or pulmonary rehabilitation but there was some preference for the disease-specific POMs; however, some of these instruments lose their discriminatory power at the end of the rehabilitation period. This literature review found that a Likert scale is more responsive than a dichotomous scale and that a simple questionnaire is more responsive in a pre- to post-setting than a complex questionnaire.

Introduction: Traditional behavioural weight loss trials targeting improvements in physical activity and diet are modestly effective. It has been suggested that sleep may have a role in weight loss and maintenance. Improving sleep health in combination with physical activity and dietary behaviours may be one strategy to enhance traditional behavioural weight loss trials. Yet the efficacy of a weight loss intervention concurrently targeting improvements in physical activity, dietary and sleep behaviours remains to be tested., Methods and Analysis: The primary aim of this three-arm randomised controlled trial is to examine the efficacy of a multicomponent m-Health behaviour change weight loss intervention relative to a waitlist control group. The secondary aims are to compare the relative efficacy of a physical activity, dietary behaviour and sleep intervention (enhanced intervention), compared with a physical activity and dietary behaviour only intervention (traditional intervention), on the primary outcome of weight loss and secondary outcomes of waist circumference, glycated haemoglobin, physical activity, diet quality and intake, sleep health, eating behaviours, depression, anxiety and stress and quality of life. Assessments will be conducted at baseline, 6 months (primary endpoint) and 12 months (follow-up). The multicomponent m-Health intervention will be delivered using a smartphone/tablet 'app', supplemented with email and SMS and individualised in-person dietary counselling. Participants will receive a Fitbit, body weight scales to facilitate self-monitoring, and use the app to access educational material, set goals, self-monitor and receive feedback about behaviours. Generalised linear models using an analysis of covariance (baseline adjusted) approach will be used to identify between-group differences in primary and secondary outcomes, following an intention-to-treat principle., Ethics and Dissemination: The Human Research Ethics Committee of The University of Newcastle Australia provided approval: H-2017-0039. Findings will be disseminated via publication in peer-reviewed journals, conference presentations, community presentations and student theses., Trial Registration Number: ACTRN12617000735358; UTN1111-1219-2050., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Treatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial., Patients and Methods: Patients were randomized 2 : 1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup., Results: Among 131 (trabectedin = 94; dacarbazine = 37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; P = 0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5 months, respectively; hazard ratio (HR)=0.40; P = 0.0002] but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; P = 0.18) or ORR (9% versus 3%, respectively; P = 0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population., Conclusions: This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients., Trial Registration: www.clinicaltrials.gov, NCT01343277.

Acute liver failure is a critical condition characterized by global hepatocyte death and often time needs a liver transplantation. Such treatment is largely limited by donor organ shortage. Stem cell therapy offers a promising option to patients with acute liver failure. Yet, therapeutic efficacy and feasibility are hindered by delivery route and storage instability of live cell products. We fabricated a nanoparticle that carries the beneficial regenerative factors from mesenchymal stem cells and further coated it with the membranes of red blood cells to increase blood stability. Unlike uncoated nanoparticles, these particles promote liver cell proliferation in vitro and have lower internalization by macrophage cells. After intravenous delivery, these artificial stem cell analogs are able to remain in the liver and mitigate carbon tetrachloride-induced liver failure in a mouse model, as gauged by histology and liver function test. Our technology provides an innovative and off-the-shelf strategy to treat liver failure.

Objective: Cognitive-behavioral therapy for insomnia (CBT-I) is recognized as the first-choice intervention for insomnia. One of the best-known advantages of CBT-I in comparison with pharmacotherapy is its long-term effect. However, only few studies have assessed its benefits with follow-up periods of longer than three years. In this clinical case series study we aimed to describe the long-term effects of group CBT-I after a mean 7.8 ± 1.6 years of follow-up (range 4-10 years)., Methods: A total of 292 insomnia disorder (ID) patients were consecutively enrolled at the Sleep Disorders Center of San Raffaele Hospital, Milan; 123 patients (82 (66.7%) females and 41 (33.3%) males, mean age 40.59 ± 11.89 years) completed the follow-up evaluation within a range of 4-10 years., Results: In the 258 patients who completed the treatment, insomnia severity index (ISI) total score improved significantly as well as all variables of the sleep diaries. Using ISI as the primary outcome, we demonstrated that the effect of CBT-I is maintained up to 10 years after the end of treatment. Furthermore, we found that patients that used only CBT-I techniques to deal with relapses were the ones with better outcomes, in particular compared to the patients that re-used medications., Conclusion: To the best of our knowledge this is the longest follow-up evaluation in the literature, both for group and individual CBT-I. These findings have an important clinical implication both suggesting and confirming that CBT-I can be considered the treatment of choice for insomnia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson's disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease's (AD). Although AD is reported as a possible development in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations.

Women with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about treatment-related central neurotoxicity in this population. The goal of this cross-sectional study was to assess brain structure and function and neurocognitive abilities in patients with ovarian cancer following first-line chemotherapy. Eighteen patients with ovarian, peritoneal and fallopian tube cancer and eighteen healthy controls matched for gender, age and education participated in the study. The patients were evaluated 1-4 months following completion of first-line taxane/platinum chemotherapy. All participants underwent structural and functional magnetic resonance imaging (MRI), and completed neuropsychological tests of attention, memory and executive functions. Neuroimaging assessments included voxel-based morphometry (VBM) for measuring gray matter (GM) volume, and functional MRI (fMRI) during the N-back working memory task. The results of VBM showed that patients had significantly reduced GM volume compared to healthy controls in the right middle/superior frontal gyrus, and in the left supramarginal gyrus and left inferior parietal lobule. fMRI results indicated significantly decreased activation in patients relative to healthy controls in the left middle frontal gyrus and left inferior parietal lobule during the N-back task (1/2/3-back >0-back). There were no statistically significant differences between the two groups on the neuropsychological tests. This is the first study showing structural and functional alterations involving frontal and parietal regions in patients with ovarian cancer treated with first-line chemotherapy. These findings are congruent with studies involving women with breast cancer, and provide additional supporting evidence for central neurotoxicity associated with taxane/platinum chemotherapy.

Stem cell transplantation is currently implemented clinically but is limited by low retention and engraftment of transplanted cells and the adverse effects of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Here, we demonstrate the safety and efficacy of encapsulating human cardiac stem cells (hCSCs) in thermosensitive poly(N-isopropylacrylamine-co-acrylic acid) or P(NIPAM-AA) nanogel in mouse and pig models of myocardial infarction (MI). Unlike xenogeneic hCSCs injected in saline, injection of nanogel-encapsulated hCSCs does not elicit systemic inflammation or local T cell infiltrations in immunocompetent mice. In mice and pigs with acute MI, injection of encapsulated hCSCs preserves cardiac function and reduces scar sizes, whereas injection of hCSCs in saline has an adverse effect on heart healing. In conclusion, thermosensitive nanogels can be used as a stem cell carrier: the porous and convoluted inner structure allows nutrient, oxygen, and secretion diffusion but can prevent the stem cells from being attacked by immune cells.

Idiopathic pulmonary fibrosis is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix causing lung distortions and dysfunctions. The prognosis after detection is merely 3-5 years and the only two Food and Drug Administration-approved drugs treat the symptoms, not the disease, and have numerous side effects. Stem cell therapy is a promising treatment strategy for pulmonary fibrosis. Current animal and clinical studies focus on the use of adipose or bone marrow-derived mesenchymal stem cells. We, instead, have established adult lung spheroid cells (LSCs) as an intrinsic source of therapeutic lung stem cells. In the present study, we compared the efficacy and safety of syngeneic and allogeneic LSCs in immuno-competent rats with bleomycin-induced pulmonary inflammation in an effort to mitigate fibrosis development. We found that infusion of allogeneic LSCs reduces the progression of inflammation and fibrotic manifestation and preserves epithelial and endothelial health without eliciting significant immune rejection. Our study sheds light on potential future developments of LSCs as an allogeneic cell therapy for humans with pulmonary fibrosis. Stem Cells Translational Medicine 2017;9:1905-1916., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background: Delirium is an acute state of brain dysfunction characterised by fluctuating inattention and cognitive disturbances, usually due to illness. It occurs commonly in the intensive care unit (ICU), and it is associated with greater morbidity and mortality. It is likely that disturbances of sleep and of the day-night cycle play a significant role. Melatonin is a naturally occurring, safe and cheap hormone that can be administered to improve sleep. The main aim of this trial will be to determine whether prophylactic melatonin administered to critically ill adults, when compared with placebo, decreases the rate of delirium., Methods: This trial will be a multi-centre, randomised, placebo-controlled study conducted in closed ICUs in Australia. Our aim is to enrol 850 adult patients with an expected ICU length of stay (LOS) of 72 h or more. Eligible patients for whom there is consent will be randomised to receive melatonin 4 mg enterally or placebo in a 1:1 ratio according to a computer-generated randomisation list, stratified by site. The study drug will be indistinguishable from placebo. Patients, doctors, nurses, investigators and statisticians will be blinded. Melatonin or placebo will be administered once per day at 21:00 until ICU discharge or 14 days after enrolment, whichever occurs first. Trained staff will assess patients twice daily to determine the presence or absence of delirium using the Confusion Assessment Method for the ICU score. Data will also be collected on demographics, the overall prevalence of delirium, duration and severity of delirium, sleep quality, participation in physiotherapy sessions, ICU and hospital LOS, morbidity and mortality, and healthcare costs. A subgroup of 100 patients will undergo polysomnographic testing to further evaluate the quality of sleep., Discussion: Delirium is a significant issue in ICU because of its frequency and associated poorer outcomes. This trial will be the largest evaluation of melatonin as a prophylactic agent to prevent delirium in the critically ill population. This study will also provide one of the largest series of polysomnographic testing done in ICU., Trial Registration: Australian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471 . Registered on 20 December 2015.

Stem cells possess the ability to home in and travel to damaged tissue when injected intravenously. For the cells to exert their therapeutic effect, they must cross the blood vessel wall and enter the surrounding tissues. The mechanism of extravasation injected stem cells employ for exit has yet to be characterized. Using intravital microscopy and a transgenic zebrafish line Tg(fli1a:egpf) with GFP-expressing vasculature, we documented the detailed extravasation processes in vivo for injected stem cells in comparison to white blood cells (WBCs). While WBCs left the blood vessels by the standard diapedesis process, injected cardiac and mesenchymal stem cells underwent a distinct method of extravasation that was markedly different from diapedesis. Here, the vascular wall undergoes an extensive remodeling to allow the cell to exit the lumen, while the injected cell remains distinctively passive in activity. We termed this process Angio-pello-sis, which represents an alternative mechanism of cell extravasation to the prevailing theory of diapedesis. Stem Cells 2017;35:170-180 Video Highlight: https://youtu.be/i5EI-ZvhBps., (© 2016 AlphaMed Press.)

High-cost, medically complex patients have been a challenging population to manage in the US health care system, in terms of both improving health outcomes and containing costs. This paper evaluated the economic impact of Care One, an intensive care management program (data analysis, evaluation, empanelment, specialist disease management, nurse case management, and social support) designed to target the most expensive 1% of patients in a university health care system. Data were collected for a cohort of high-cost, medically complex patients (N = 753) who received care management and a control group (N = 794) of similarly complex health system users who did not receive access to the program. A pre-post empirical model estimated the Care One program to be associated with a per-patient reduction in billed charges of $92,227 (95% confidence interval [CI]: $83,988 to $100,466). A difference-in-difference model, which utilized the control group, estimated a per-patient reduction in billing charges of $44,504 (95% CI: $29,195 to $59,813). Results suggest that care management for high-cost, medically complex patients in primary care can reduce costs compared to a control group. In addition, significant reversion to the mean is found, providing support for the use of a difference-in-difference estimator when evaluating health programs for high-cost, medically complex patients.

Background: Obstructive sleep apnoea (OSA) affects up to 28 % of the adult population in Western countries. The detection and management of OSA by general practitioners (GPs) can be poor. The study aimed to examine what influence enhanced invitations had on uptake of on-line learning modules for OSA by GPs, and whether recent referrals of patients to sleep specialists influenced uptake., Methods: Practicing GPs in regional Australia were identified and randomised to receive either an enhanced or standard invitation letter to a new on-line education module for OSA. The enhanced letter included indication that the module was eligible for professional accreditation and described the prevalence and burden of sleep disorders. Some included extra emphasis if the GP had recently referred a patient for diagnostic investigation of OSA. Two reminder letters were sent., Results: Of 796 eligible GPs who received the letters, sixteen (2 %) accessed the website and four completed the modules over the four-month study period. GPs who received an enhanced invitation letter were not significantly more likely to access the website compared to GPs who received the standard invitation letter. Recent referral of a patient for diagnostic investigation was also not a significant factor in influencing use of the module., Conclusion: GP interest in on-line education about OSA appears low, and emphasis of relevant recent past patient(s) and the opportunity for professional education points was not successful in increasing engagement. There is a need to identify effective approaches to improving the detection and management of OSA in general practice.

Obstructive sleep apnea affects 20% of the adult population. Weight control is considered the best non-medical means of managing the condition, therefore improving nutritional knowledge in individuals may be an appropriate strategy. This study aimed to describe the relationship between nutritional knowledge and: (i) sleep disorder severity; (ii) body mass index; and (iii) demographic characteristics in persons suspected of obstructive sleep apnea. Nutrition knowledge scores were also compared with the general population. Consecutive newly-referred patients attending the sleep laboratory for diagnostic polysomnography were invited to participate. Those who consented (n = 97) were asked to complete a touchscreen survey. Apnea-hypopnea index to measure sleep disorder severity and anthropometric measurements were obtained from the clinic. A quarter of participants were diagnosed with severe obstructive sleep apnea; and a majority (88%) were classed as being overweight or obese. The overall mean nutrition knowledge score was 58.4 ± 11.6 (out of 93). Nutrition knowledge was not associated with sleep disorder severity, body mass index or gender. The only significant difference detected was in relation to age, with older (≥35 years) participants demonstrating greater knowledge in the 'food choices' domain compared with their younger counterparts (18-34 years; P < 0.030). Knowledge scores were similar to the general population. The findings suggest that nutrition knowledge alone is not an important target for weight control interventions for people with obstructive sleep apnea. However, given the complexities of sleep disorders, it may complement other strategies., (© 2016 European Sleep Research Society.)